Cognitive dysfunction, social behavior disorder, cerebellar ataxia, and atypical brain FDG-PET presentation in spinocerebellar ataxia 17: a case report.

BACKGROUND: Spinocerebellar ataxia 17 (SCA17) is a rare autosomal dominant form of inherited ataxia, caused by heterozygous trinucleotide repeat expansions encoding glutamine in the TATA box-binding protein (TBP) gene. CASE DESCRIPTION: We describe the clinical history, neuropsychological, and neuroimaging findings of a 42-year-old patient who presented for medical attention showing prevalent behavioral and cognitive problems along with progressively worsening gait disturbances. The patient's family history indicated the presence of SCA17 in the maternal lineage. Genetic analysis confirmed a heterozygous 52-CAG pathological expansion repeat in TBP (normal interval, 25-40 CAG. Brain 18-fluorodeoxyglucose positron emission tomography (FDG-PET) showed bilateral hypometabolism in the sensorimotor cortex, with a slight predominance on the right, as well as in the striatal nuclei and thalamic hypermetabolism, a finding similar to what is observed in Huntington's disease. The patient also underwent neuropsychological evaluation, which revealed mild cognitive impairment and difficulties in social interaction and understanding other's emotions (Faux Pas Test and Reading the Mind in the Eyes Test). CONCLUSION: Our report emphasizes the importance of considering SCA17 as a possible diagnosis in patients with a prevalent progressive cognitive and behavioral disorders, even with a pattern of FDG-PET hypometabolism not primarily indicative of this disease.

Robot-assisted surgery and artificial intelligence-based tumour diagnostics: social preferences with a representative cross-sectional survey.

BACKGROUND: The aim of this study was to assess social preferences for two different advanced digital health technologies and investigate the contextual dependency of the preferences. METHODS: A cross-sectional online survey was performed among the general population of Hungary aged 40 years and over. Participants were asked to imagine that they needed a total hip replacement surgery and to indicate whether they would prefer a traditional or a robot-assisted (RA) hip surgery. To better understand preferences for the chosen method, the willingness to pay (WTP) method was used. The same assessment was conducted for preferences between a radiologist's and AI-based image analysis in establishing the radiological diagnosis of a suspected tumour. Respondents' electronic health literacy was assessed with the eHEALS questionnaire. Descriptive methods were used to assess sample characteristics and differences between subgroups. Associations were investigated with correlation analysis and multiple linear regressions. RESULTS: Altogether, 1400 individuals (53.7% female) with a mean age of 58.3 (SD = 11.1) years filled in the survey. RA hip surgery was chosen by 762 (54.4%) respondents, but only 470 (33.6%) chose AI-based medical image evaluation. Those who opted for the digital technology had significantly higher educational levels and electronic health literacy (eHEALS). The majority of respondents were willing to pay to secure their preferred surgical (surgeon 67.2%, robot-assisted: 68.8%) and image assessment (radiologist: 70.9%; AI: 77.4%) methods, reporting similar average amounts in the first (p = 0.677), and a significantly higher average amount for radiologist vs. AI in the second task (p = 0.001). The regression showed a significant association between WTP and income, and in the hip surgery task, it also revealed an association with the type of intervention chosen. CONCLUSIONS: Individuals with higher education levels seem to accept the advanced digital medical technologies more. However, the greater openness for RA surgery than for AI image assessment highlights that social preferences may depend considerably on the medical situation and the type of advanced digital technology. WTP results suggest rather firm preferences in the great majority of the cases. Determinants of preferences and real-world choices of affected patients should be further investigated in future studies.

Two is company: The posterior cerebellum and sequencing for pairs versus individuals during social preference prediction.

Previous studies have identified that the posterior cerebellum, which plays a role in processing temporal sequences in social events, is consistently and robustly activated when we predict future action sequences based on personality traits (Haihambo Haihambo et al. Social Cognitive and Affective Neuroscience 17(2), 241-251, 2022) and intentions (Haihambo et al. Cognitive, Affective, and Behavioral Neuroscience 23(2), 323-339, 2023). In the current study, we investigated whether these cerebellar areas are selectively activated when we predict the sequences of (inter)actions based on protagonists' preferences. For the first time, we also compared predictions based on person-to-person interactions or single person activities. Participants were instructed to predict actions of one single or two interactive protagonists by selecting them and putting them in the correct chronological order after being informed about one of the protagonists' preferences. These conditions were contrasted against nonsocial (involving objects) and nonsequencing (prediction without generating a sequence) control conditions. Results showed that the posterior cerebellar Crus 1, Crus 2, and lobule IX, alongside the temporoparietal junction and dorsal medial prefrontal cortex were more robustly activated when predicting sequences of behavior of two interactive protagonists, compared to one single protagonist and nonsocial objects. Sequence predictions based on one single protagonist recruited lobule IX activation in the cerebellum and more ventral areas of the medial prefrontal cortex compared to a nonsocial object. These cerebellar activations were not found when making predictions without sequences. Together, these findings suggest that cerebellar mentalizing areas are involved in social mentalizing processes which require temporal sequencing, especially when they involve social interactions, rather than behaviors of single persons.

The Dispositional Essence of Proactive Social Preferences: The Dark Core of Personality vis-à-vis 58 Traits.

Individuals differ in how they weigh their own utility versus others'. This tendency codefines the dark factor of personality (D), which is conceptualized as the underlying disposition from which all socially and ethically aversive (dark) traits arise as specific, flavored manifestations. We scrutinize this unique theoretical notion by testing, for a broad set of 58 different traits and related constructs, whether any predict how individuals weigh their own versus others' utility in proactive allocation decisions (i.e., social value orientations) beyond D. These traits and constructs range from broad dimensions (e.g., agreeableness), to aversive traits (e.g., sadism) and beliefs (e.g., normlessness), to prosocial tendencies (e.g., compassion). In a large-scale longitudinal study involving the assessment of consequential choices (median N = 2,270; a heterogeneous adult community sample from Germany), results from several hundred latent model comparisons revealed that no meaningful incremental variance was explained beyond D. Thus, D alone is sufficient to represent the social preferences inherent in socially and ethically aversive personality traits.

Deficiency of Autism-Related Gene Dock4 Leads to Impaired Spatial Memory and Hippocampal Function in Mice at Late Middle Age.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that lasts lifelong and causes noticeably higher premature mortality. Although the core symptoms and other behavioral deficits of ASD can persist or be deteriorated from early development to old age, how aging affects the behaviors and brain anatomy in ASD is largely unknown. DOCK4 is an ASD risk gene highly expressed in the hippocampus, and Dock4 knockout (KO) mice display ASD-like behaviors in adulthood (4- to 6-month-old). In this study, we evaluated the behavioral and hippocampal pathological changes of late-middle-aged (15- to 17-month-old) Dock4 male KO mice. Aged Dock4 KO mice continuously showed similar social deficit, elevated anxiety, and disrupted object location memory as observed in the adulthood, when compared to their wild-type (WT) littermates. Notably, Dock4 KO mice displayed an age-related decline of hippocampal dependent spatial memory, showing decreased spatial memory in Barnes maze than their WT littermates at late middle age. Morphological analysis from WT and Dock4 KO littermates revealed that Dock4 deficiency led to decreased mature neurons and oligodendrocytes but increased astrocytes in the hippocampus of late-middle-aged mice. Together, we report that ASD-like behaviors mostly persist into late-middle age in Dock4 KO mice, with specific alterations of spatial memory and hippocampal anatomy by age, thus providing new evidence for understanding age differences in behavioral deficits of ASD.

Association Between Children's Empathy and Depression: The Moderating Role of Social Preference.

Although empathy is typically an adaptive characteristic of children, extreme empathy alone or in combination with a negative environment may contribute to a risk of depression. The present study comprehensively investigated the associations between the three constructs of empathy and depression in children, as well as the potential moderating effect of peer relationships (i.e., social preference) on this association. A total of 1223 children (mean age = 10.50 ± .93 years) completed questionnaires on empathy and depression, and social preference was nominated by their peers. Cognitive empathy and positive empathy exerted a positive quadratic effect on depression, while negative empathy had a positive linear association with depression. For children with a low social preference, all three empathy constructs were positively quadratically correlated with depression, extremely high and low empathy were associated with increased depression, and moderate empathy was associated with the lowest level of depression. For children with a high social preference, higher positive empathy was associated with lower depression.

Clique Hierarchy Moderates the Association between Social Preference and Defending Behaviors in Early Adolescence: The Role of Gender Differences.

Although social preference promotes adolescents' defending behaviors, its potential mechanisms across gender cliques remain unclear from the group dynamic perspective. This study investigated 2470 Chinese early adolescents (49% girls, Mage = 14.40, SD = 0.58) to explore how social preference and clique hierarchy are associated with defending behaviors and whether these associations differ across gender-specific cliques. The results revealed that social preference was positively related to defending behaviors in boys' cliques, but negatively in girls' cliques. Furthermore, the association was strengthened by hierarchization in boys' cliques but was weakened in girls' cliques, while the status structure strengthened the association in boys' but not girls' cliques. These findings hold crucial implications for understanding and promoting defending behaviors among adolescents.

Understanding the Function of Challenging Behavior and Related Intervention and Strategies.

People with intellectual disability or related neurodevelopmental disorders may present the full range of psychiatric and behavioral disorders seen in the general population. In fact, research has shown that they are more susceptible to presenting psychiatric disorders and/or challenging behaviors. When a person with intellectual disability or a related neurodevelopmental disorder exhibits challenging behaviors, it is important to identify the underlying causes. These causes may be multifactorial. In this article we briefly discuss the elements of conducting a comprehensive assessment of the function of presenting challenging behaviors. This multifunctional assessment must include assessing for the presence of physical health problems, an undiagnosed oral health problem, psychiatric disorders, the level of sensory stimuli in the environment, and conclude with an evaluation of antecedents and consequences that may be contributing to a learned behavior. An important resultant of the information gained from this comprehensive functional assessment are intervention strategies that should target the function of the challenging behaviors and lead to reducing these challenging behaviors by addressing the need that they serve.

A genetic basis for friendship? Homophily for membrane-associated PDE11A-cAMP-CREB signaling in CA1 of hippocampus dictates mutual social preference in male and female mice.

Although the physical and mental benefits of friendships are clear, the neurobiological mechanisms driving mutual social preferences are not well understood. Studies in humans suggest friends are more genetically similar, particularly for targets within the 3',5'-cyclic adenosine monophosphate (cAMP) cascade. Unfortunately, human studies can not provide conclusive evidence for such a biological driver of friendship given that other genetically related factors tend to co-segregate with friendship (e.g., geographical proximity). As such, here we use mice under controlled conditions to test the hypothesis that homophily in the cAMP-degrading enzyme phosphodiesterase 11A4 (PDE11A4) can dictate mutual social preference. Using C57BL/6J and BALB/cJ mice in two different behavioral assays, we showed that mice with two intact alleles of Pde11a prefer to interact with Pde11 wild-type (WT) mice of the same genetic background over knockout (KO) mice or novel objects; whereas, Pde11 KO mice prefer to interact with Pde11 KO mice over WT mice or novel objects. This mutual social preference was seen in both adult and adolescent mice, and social preference could be eliminated or artificially elicited by strengthening or weakening PDE11A homodimerization, respectively. Stereotactic delivery of an isolated PDE11A GAF-B domain to the mouse hippocampus revealed the membrane-associated pool of PDE11A-cAMP-CREB signaling specifically within the CA1 subfield of hippocampus is most critical for regulating social preference. Our study here not only identifies PDE11A homophily as a key driver of mutual social preference across the lifespan, it offers a paradigm in which other mechanisms can be identified in a controlled fashion.

Conditioned social preference and reward value of activating oxytocin-receptor-expressing ventral tegmental area neurons following repeated daily binge ethanol intake.

BACKGROUND: Individuals with alcohol use disorder (AUD) exhibit a disruption of social behavior and dysregulation of oxytocin signaling in the brain, possibly reflecting decreased activation of oxytocin receptors (OxTRs) in reward pathways in response to social stimuli. We hypothesize that daily binge ethanol intake causes a deficit in social reward and oxytocin signaling in the ventral tegmental area (VTA). METHODS: After 9 weeks of daily binge ethanol intake (blood ethanol concentration >80 mg%), OxTR-cre mice underwent conditioned place preference for social reward. Separate groups of mice were tested for the effects of binge ethanol on voluntary social interactions, food reward, locomotion, and anxiety-like behaviors. A subset of mice underwent transfection of OxTR-expressing VTA neurons (VTAOxtr ) with a light-sensitive opsin, followed by operant training to respond to light delivered to VTA. RESULTS: Ethanol-naïve male mice increased the time spent on the side previously paired with novel mice while ethanol-treated mice did not. Binge ethanol did not affect conditioned place preference for food reward in males, but this response was weakened in ethanol-treated females. Ethanol treatment also caused a sex-specific impairment of voluntary social interactions with novel mice. There were minimal differences between groups in measures of anxiety and locomotion. Ethanol-naïve mice had significantly greater operant responding for activation of VTAOxtr than sham-transfected mice but ethanol-treated mice did not. There was no difference in the number of VTAOxtr after binge ethanol. CONCLUSIONS: Daily binge ethanol causes social reward deficits that cannot be explained by nonspecific effects on other behaviors, at least in males. Only ethanol-naïve mice exhibited positive reinforcement caused by activation of VTAOxtr while daily binge ethanol did not alter the number of VTAOxtr in either males or females. Thus, subtle dysregulation of VTAOxtr function may be related to the social reward deficits caused by daily binge ethanol.

Effects of galantamine on social interaction impairments in cholecystokinin receptor-2 overexpression mice.

We examined whether galantamine (GAL), a cholinesterase inhibitor and allosteric potentiating ligand for α7 nicotinic acetylcholine receptor (nAChR), had an impact on emotional abnormalities in forebrain-specific cholecystokinin receptor-2 overexpressed transgenic mice. Treatment with GAL (1 mg/kg, s.c.) attenuated the decrease of social interaction time, but failed to attenuate anxiety-like behavior in the elevated plus-maze test. The effect of GAL was blocked by an α7 nAChR antagonist, methyllycaconitine (3 mg/kg, i.p.). These results suggest that GAL improved social interaction impairments via α7 nAChR and could be useful to treat sociability-related emotional abnormalities.

"This kid looks like he has everything": 3- to 11-year-old children's concerns for fairness and social preferences when peers differ in social class and race.

This study investigated 3- to 11-year-old US children's (N = 348) perceptions of access to resources, social group preferences, and resource distribution decisions and reasoning when hypothetical peers differed in social class (poor or rich) and race (Black or White). Data were collected in 2019. The sample reflected the region where data were collected in terms of gender (44% girls, 30% boys, 1% another identity) and race and ethnicity (46% White, 10% multiracial or multiethnic, 9% Black, 5% Latinx, 2% Asian, 3% another identity), and parents reported a higher average level of education than the regional average. Results revealed both marked age differences in children's perceptions, preferences, decisions, and reasoning and specific combinations of peer group memberships that were especially likely to receive preferential treatment. With age, children perceived that rich peers had greater access to resources than poor peers, but when both peers were poor, White peers were perceived to have more resources than Black peers. Social group preferences changed with age, from mixed social class and racial group preferences, to preferences for rich peers, to dislike for rich peers. Resource allocation decisions and reasoning reflected both social group and fairness concerns: young children distributed more to White peers especially if they were also rich, participants in middle childhood explicitly favored rich peers regardless of their race, and older children distributed more to poor peers and reasoned about either moral concerns for equity or social class stereotypes. Thus, overall, younger children's responses often reflected broader economic and racial inequalities while older children often sought to create more equity, though not always for moral reasons.

A Call for Drug Therapies for the Treatment of Social Behavior Disorders in Dementia: Systematic Review of Evidence and State of the Art.

Growing evidence supports the presence of social cognition deficits and social behavior alterations in major and minor neurocognitive disorders (NCDs). Even though the ability to identify socio-emotional changes has significantly improved in recent years, there is still no specific treatment available. Thus, we explored evidence of drug therapies targeting social cognition alterations in NCDs. Papers were selected according to PRISMA guidelines by searching on the PubMed and Scopus databases. Only papers reporting information on pharmacological interventions for the treatment of social cognition and/or social behavioral changes in major and/or minor NCDs were included. Among the 171 articles entered in the paper selection, only 9 papers were eligible for the scope of the review. Trials testing pharmacological treatments for socio-emotional alterations in NCDs are poor and of low-medium quality. A few attempts with neuroprotective, psychoactive, or immunomodulating drugs have been made. Oxytocin is the only drug specifically targeting the social brain that has been tested with promising results in frontotemporal dementia. Its beneficial effects in long-term use have yet to be evaluated. No recommendation can currently be provided. There is a long way to go to identify and test effective targets to treat social cognition changes in NCDs for the ultimate benefit of patients and caregivers.

Long-term consequences of peri-adolescent social isolation on social preference, anxiety-like behaviour, and vasopressin neural circuitry of male and female rats.

Social isolation during the juvenile and adolescent stages (peri-adolescent social isolation) can have long-term consequences for behavioural and neural development. Most of this research, however, has relied on data from males, and very few studies have included both sexes. The present study investigated the impact of peri-adolescent social isolation on social preference, anxiety-like behaviour, and vasopressin neural circuitry of male and female Long Evans rats. Rats were either housed alone for 3 weeks beginning at weaning (Isolated) or in groups (Group-housed). In adulthood, rats were tested in social preference, open field, marble burying, and light/dark box tests, and brains were processed for vasopressin immunohistochemistry. Isolated males exhibited a lower social preference score and spent more time in the light zone of the light/dark box than their group-housed counterparts. Isolated and Group-housed females did not differ in these measures. Peri-adolescent social isolation did not alter vasopressin fibre density in target areas known to influence social and anxiety-like behaviours (the lateral septum or lateral habenula), but increased fibre density in an output pathway of the circadian pacemaker (projections to the paraventricular nucleus of the thalamus); an effect detected across both sexes. A previously unreported sex difference was also detected for vasopressin fibre density in the paraventricular nucleus of the thalamus (females > males). These findings demonstrate long-term consequences of peri-adolescent social isolation on social preference, anxiety-like behaviour, and the circadian vasopressin pathway and suggest that socio-affective development of males is more vulnerable to social stressors during the juvenile and adolescent stages.

LF-rTMS ameliorates social dysfunction of FMR1-/- mice via modulating Akt/GSK-3ß signaling.

Autism spectrum disorders (ASD) are a group of neurological disorders which affect approximately 1% of children around the world. Social dysfunction is one of the two core syndromes of ASD, and still lacks effective treatment. Transcranial magnetic stimulation (TMS) is a noninvasive and safe procedure that uses magnetic fields to modulate neural activity. Whether it were effective in modulating social function remains unclear. By using 3-chamber test, ultrasonic vocalization recording and Western-blotting, we demonstrated that FMR1 (fragile X mental retardation protein) mutant mice, a model of ASD, exhibited obvious defects in social preference and ultrasonic communication. In addition, we detected increase of p-Akt (S473) and p-GSK-3ß (S9), and decrease of p-PSD-95 (T19) in the anterior cingulate cortex (ACC) of FMR1-/- mice. Treating FMR1-/- mice with 1 Hz repetitive TMS (rTMS) exerted a long lasting effect in improving both the ultrasonic communication and social preference, as well as restoring the levels of Akt/GSK-3ß activity and spine density in the FMR1-/-ACC. Our data, for the first time, demonstrated a beneficial effect of low frequency rTMS (LF-rTMS) on the social function of FMR1-/- mice and an involvement of Akt/GSK-3ß signaling in this process, indicating LF-rTMS as a potential therapeutic strategy for ASD patients.

Chemogenetic manipulation of the bed nucleus of the stria terminalis counteracts social behavioral deficits induced by early life stress in C57BL/6J mice.

Trauma during critical periods of development can induce long-lasting adverse effects. To study neural aberrations resulting from early life stress (ELS), many studies utilize rodent maternal separation, whereby pups are intermittently deprived of maternal care necessary for proper development. This can produce adulthood behavioral deficits related to anxiety, reward, and social behavior. The bed nucleus of the stria terminalis (BNST) encodes aspects of anxiety-like and social behaviors, and also undergoes developmental maturation during the early postnatal period, rendering it vulnerable to effects of ELS. Mice underwent maternal separation (separation 4 hr/day during postnatal day (PD)2-5 and 8 hr/day on PD6-16) with early weaning on PD17, which induced behavioral deficits in adulthood performance on two-part social interaction task designed to test social motivation (choice between a same-sex novel conspecific or an empty cup) and social novelty preference (choice between the original-novel conspecific vs. a new-novel conspecific). We used chemogenetics to non-selectively silence or activate neurons in the BNST to examine its role in social motivation and social novelty preference, in mice with or without the history of ELS. Manipulation of BNST produced differing social behavior effects in non-stressed versus ELS mice; social motivation was decreased in non-stressed mice following BNST activation, but unchanged following BNST silencing, while ELS mice showed no change in social behavior after BNST activation, but exhibited enhancement of social motivation-for which they were deficient prior-following BNST silencing. Findings emphasize the BNST as a potential therapeutic target for social anxiety disorders instigated by childhood trauma.

Autism spectrum disorder and severe social impairment associated with elevated plasma interleukin-8.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an unclear etiology and pathophysiology. Previous studies have indicated that the dysregulation of cytokines may be involved in the pathogenesis of ASD and that the levels of cytokines may serve as potential biomarkers of this disorder. METHODS: The current study employed a family triad-based case-control design to study the levels of plasma cytokines in families with ASD (n = 45 triads) and controls (n = 38 triads) with a Human Cytokine Twenty-Five-Plex Kit. The Social Responsiveness Scale (SRS) was used to measure social impairment of ASD children. RESULTS: After controlling for the levels of parental cytokines, we identified that interferon-α (IFN-α), interleukin-7 (IL-7), IL-8, IFN-γ-inducible protein-10, and macrophage inflammatory protein-1ß were associated with ASD, and IL-8 was the only cytokine also associated with the levels of both parental cytokines in the offspring-parents regression analysis and three subdomains of SRS (social awareness, cognition, and motivations) in the children with ASD. The receiver operating characteristic curve showed that the log-transformed IL-8 level discriminated children with autism from controls with an area under the curve of 0.858 (95% confidence interval: 0.777-0.939). CONCLUSIONS: Our study suggests that IL-8 is a potential biomarker for ASD and may be involved in the pathogenesis of ASD. IMPACT: The study suggests that IL-8 is a promising biomarker for ASD and may be involved in the pathogenesis of ASD. Only a very few studies have reported the parental cytokine levels. The significant strength of this article is that we applied the family triad-based approach to explore cytokine levels in families with autism and controls. There are no objective biomarkers, making the accurate diagnosis, prognostic prediction and effective treatment difficult, and our study provides promising results.

Early adolescent Rai1 reactivation reverses transcriptional and social interaction deficits in a mouse model of Smith-Magenis syndrome.

Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), a syndromic autism spectrum disorder associated with craniofacial abnormalities, intellectual disability, and behavioral problems. There is currently no cure for SMS. Here, we generated a genetic mouse model to determine the reversibility of SMS-like neurobehavioral phenotypes in Rai1 heterozygous mice. We show that normalizing the Rai1 level 3-4 wk after birth corrected the expression of genes related to neural developmental pathways and fully reversed a social interaction deficit caused by Rai1 haploinsufficiency. In contrast, Rai1 reactivation 7-8 wk after birth was not beneficial. We also demonstrated that the correct Rai1 dose is required in both excitatory and inhibitory neurons for proper social interactions. Finally, we found that Rai1 heterozygous mice exhibited a reduction of dendritic spines in the medial prefrontal cortex (mPFC) and that optogenetic activation of mPFC neurons in adults improved the social interaction deficit of Rai1 heterozygous mice. Together, these results suggest the existence of a postnatal temporal window during which restoring Rai1 can improve the transcriptional and social behavioral deficits in a mouse model of SMS. It is possible that circuit-level interventions would be beneficial beyond this critical window.

Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Lifelong consequences of brain injuries during development: From risk to resilience.

Traumatic brain injuries in children represent a major public health issue and even relatively mild injuries can have lifelong consequences. However, the outcomes from these injuries are highly heterogeneous, with most individuals recovering fully, but a substantial subset experiencing prolonged or permanent disabilities across a number of domains. Moreover, brain injuries predispose individuals to other kinds of neuropsychiatric and somatic illnesses. Critically, the severity of the injury only partially predicts subsequent outcomes, thus other factors must be involved. In this review, we discuss the psychological, social, neuroendocrine, and autonomic processes that are disrupted following traumatic brain injury during development, and consider the mechanisms the mediate risk or resilience after traumatic brain injury in this vulnerable population.